Focal segmental glomerulosclerosis (FSGS) occurs in an idiopathic form and in association with HIV infection, both of which are more common among African Americans (AA). The pathogenesis of FSGS remains an unknown and no effective therapy has been demonstrated. We hypothesize that a gene or genes, present in people of African descent, predisposes to FSGS following exposure to particular environmental factors, in this case, HIV infection. In collaboration with the Kidney Disease Section, NIDDK, a multicenter study with 13 extramural sites has been initiated. We have accrued 222 AA and 89 European Americans (EA) with FSGS and 210 intravenous drug users who have been infected with HIV for at least eight years but retain normal kidney function. We are using a candidate gene approach to identify markers associated with the FSGS phenotype. In a preliminary analysis, 258 cases and controls have been genotyped for 22 diallelic candidate genes. Two polymorphic sites in the promoter and first exon of the transforming growth factor beta 1(TGFB1) gene have been shown by haplotype analysis to be associated with the FSGS phenotype. Analysis of the TGFB1 alleles has determined that the ancestral haplotype is associated with increased risk of FSGS, possibly by the up-regulation of TGF beta 1 protein. We are testing this hypothesis by measuring plasma TGF beta 1 protein levels in volunteer donors of known TGFB1 genotypes. The alu insertion/deletion (ins/del) mutation in the angiotensin converting enzyme gene ACE is also associated with FSGS (p=0.001) in AA. As there are more than 70 identified single nucleotide polymorphisms (SNPs) in the ACE gene, it is not possible to discern if the ins/del is itself affecting the causal pathway of the disease or is tracking through linkage disequilibrium the causal site. We have completed sequencing the ACE gene in FSGS cases and controls to determine haplotype structure, identify SNPs in linkage disequilibrium with the ins/del, and identify the causative haplotype alleles. This study should also provide insight into the role of ACE alleles in hypertension, an important cardiovascular risk factor disproportionality affecting AA.